Bidentate Lewis Acid-Catalyzed Inverse Electron-Demand Diels–Alder Reaction of Phthalazines and Cyclooctynes

Abstract

Herein we report a method for facilitating the inverse-electron-demand Diels–Alder reaction of 1,2-diazines and cyclooctynes by utilizing a boron-based bidentate Lewis acid catalyst. Readily available electron-deficient and electron-rich phthalazines proved to be suitable substrates in this transformation. The described method enables the facile construction of diversely substituted polycyclic aromatic hydrocarbons fused to eight-membered carbocycles.

Key words

cycloaddition - diazines - cyclooctyne - bidentate catalysis - polycyclic aromatic hydrocarbons - Diels–Alder reactions

Publication History

Received: 15 October 2023

Accepted after revision: 06 November 2023

Accepted Manuscript online:
06 November 2023

Article published online:
13 December 2023

• References and Notes

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• 19 General procedure for the BDLA-catalyzed IEDDA reaction: In a nitrogen-filled glove box, (substituted) phthalazine 1 (0.10 mmol, 1.0 equiv) and BDLA catalyst (5.0 μmol, 5.0 mol%) were suspended in anhydrous and degassed 1,4-dioxane (1.0 mL) in a 4 mL screw-cap vial with a stirrer bar. Cyclooctyne (2) or exo-BCN (1.1–3.0 equiv) was added to the mixture, and the vial was sealed and taken out of the glove box. The mixture was stirred at the given temperature for the given time. Afterwards, the reaction mixture was concentrated in vacuo. The ratio of product to unreacted phthalazine was determined by ¹H NMR spectroscopic analysis of the crude mixture. The crude mixture was purified by column chromatography (3 g of silica gel) to afford product 3 or 4
• 20 ((1r,1aR,11aS)-1a,2,3,10,11,11a-hexahydro-1H-cyclopropa[5,6]cycloocta[1,2-b]naphthalen-1-yl)methanol (4a): Yield: 13 mg (52%); colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.76–7.71 (m, 2 H), 7.56 (s, 2 H), 7.41–7.36 (m, 2 H), 3.38 (d, J = 6.5 Hz, 2 H), 3.10 (ddd, J = 14.1, 8.3, 5.7 Hz, 2 H), 2.92 (dt, J = 14.1, 5.8 Hz, 2 H), 2.59–2.45 (m, 2 H), 1.42–1.25 (m, 3 H), 0.77–0.66 (m, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 141.21 (2 C), 132.49 (2 C), 128.04 (2 C), 127.08 (2 C), 125.24 (2 C), 66.78, 33.63 (2 C), 30.16 (2 C), 29.76 (2 C), 22.03. HRMS (ESI): m/z calcd for C₁₈H₂₀ONa: 275.1406 [M + Na]⁺; found: 275.1406.